Background Appropriate patient selection is crucial to the success of bariatric surgery (BaS). The objective of this study was to identify risk factors for increased post-operative mortality in patients undergoing BaS using a nationally representative sample. Materials and methods BaS patients ≥18 years old in the United States were identified from the 2001 Nationwide Inpatient Sample (NIS). The effect of gender, age, insurance status, and need for re-operation on post-operative mortality was examined using a multivariate logistic regression model. Results A national cohort of 54,878 patients was identified with age 41 ± 0.2 years (mean ± SE), 84% women, length of stay (LOS) 3.9 ± 0.2 days, and overall mortality of 4 per 1,000 BaS patients. Mean LOS of those who died was 17.6 ± 3.7 days. Adjusting for comorbidities and demographics, men had increased likelihood of death [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.1–4.3, P < 0.05]. Compared to younger patients, those aged above 39 years had over two-fold risk of death [ages 40–49: OR 2.6, 95% CI 1.1–6.5, P < 0.05; ages 50–59: OR 4.3, 95% CI 1.7–11, P < 0.05]. Medicaid patients [OR 4.7, 95% CI 1.2–13, P < 0.05 compared to privately insured] and those requiring re-operation [OR 22, 95% CI 5.4–88, P < 0.05] had higher odds of dying. Conclusion Based on national data, risk factors for increased post-operative mortality in BaS patients include male gender, age >39 years, Medicaid insured, and need for re-operation. These data can assist in optimizing BaS patient outcomes.